Oral hypoglycemic agents such as tolbutamide have been widely used to treat diabetes-induced hyperglycemia since their clinical introduction 20 years ago. However, the use of these agents has been recently challenged by investigators who have found an increased risk of cardiovascular deaths in patients treated with the sulfonylurea. Our studies suggest that tolbutamide over the concentration range of 0.06 to 0.6 mM protects the ischemic heart; however, higher doses may have an adverse effect. The mechanism by which tolbutamide benefits the ischemic heart remains the central focus of this investigation.